Cholesterol and hair loss
Cholesterol and hair loss

NORMAL LIPID METABOLISM IS IMPORTANT FOR THE HAIR GROWTH CYCLE

Hair follicles originate from the skin, an organ whose primary function is a barrier to water loss and maintenance of the immune system by the provision for a protective barrier.  This would lead to the natural assumption that the hair follicle structure and function would be dominated by lipid components.

Lipids retain the structure of the hair fibre, lipids repel water and lipids maintain chemical messagings between keratin cells and the epidermis in which the hair fibre is housed.  Yet, in practice, little attention is paid to the importance of lipid metabolism in the normal function of the hair follicle.  In 2007, Wan et al showed ingestion of oxidised lipids induced alopecia which was reversed after removal of oxidised proteins from the diet [1].

Lipid (fat) metabolism describes the synthesis and the breaking down of lipids with in cells.  The breakdown of lipids are essential for providing energy to the cell and for the synthesis of lipids are important for the building of structural and functional lipids such as the construction of the cell membrane and fatty acids.

Lipid metabolism disorders occur when there is a disturbance in the substances involved in the breaking down and synthesising of lipids.  Disorders of lipid metabolism are associated with an increase in the concentration of blood lipids such as LDL cholesterol and triglycerides.

Disturbances in lipid metabolism impact hair follicle growth as proper lipid metabolism is essential for controlling the fluidity of keratin cells that make up the hair fibre and the lipids that are responsible for cell membrane stability.

Lipid metabolism is also essential for hormones such as testosterone and progesterone that impact the hair growth cycle.  Another important role of lipids are as signalling molecules and energy vital fuel source for keratin cells.  Without proper lipid metabolism, the structure requirements and energy needs of the keratin cell will not be met.

Fat metabolism and the hair fibre

LIPIDS ARE ESSENTIAL FOR ALL BIOLOGICAL FUNCTIONS IN THE BODY

A lipid is a molecule that is insoluble in most solvents like blood and water.   Lipids are also known as ‘fats’ and include fatty acids, waxes, hormones, sterols (such as cholesterol), fat-soluble vitamins (such as vitamin A, D, E and K), monoglycerides, diglycerides, triglycerides, ceramides and phospholipids.

Lipids that can be measured in the blood include all fat-soluble vitamins, steroid based hormones (estrogens and androgens) triglycerides and cholesterol.  By measuring these lipids, a doctor can understand how you are utilising lipids within your body.

Lipids play an important role in the regulation of keratin cell membranes, the hair growth cycle and also the quality and smooth feel of the hair fibre.  Maintaining lipid metabolism is important for the prevention of hair loss and hair regrowth after a period of hair thinning.

ABSORPTION, DIGESTION AND UTILISATION OF LIPIDS

In humans, lipids are taken up form the diet or synthesised by the liver using a process called lipogenesis.  A majority of lipids that are derived form the diet are triglycerides and cholesterol.  Since lipids are not water soluble, the liver and pancreas secrete lipases (enzymes that breakdown fats) to enable digestion in a process known as hydrolysis.

After lipid hydrolysis, the lipids are absorbed into the cells of the intestinal wall and then packaged up into packages called  and transported to the rest of the body.

Cells can use two sources of fat for energy, stored fat and dietary fats.  Lipids can be stored in adipose tissue (fat cells), this is a major energy source for living organisms.

When chylomicrons or other lipoproteins (proteins that transport lipids) enter the bodies tissue, they are broken down by lipoprotein lipases and the lipid is separated from the protein as a triglyceride.  Triglycerides then get broken down into fatty acids and glycerol before before entering the cell and any remaining cholesterol will travel through the blood to the liver with apolioprotein E.

Hair loss and lipid digestion

Appropriate digestion and absorption are required for utilisation of lipids.  Lipids are subject to hydrolysis after ingestion and transported throughout the body.

LIPIDS FORM A STRUCTURAL BARRIER TO PREVENT WATER LOSS FROM THE HAIR AND SKIN

Lipids are divided into two groups: Apolar and polar.  Triglycerides are apolar and they are stored in various cells, especially adipose tissue.  Polar lipids are structural components of cell membranes, where they participate in that formation that controls the permeability barrier of cells and the mini organs within cells.

Lipids form a lipid bilayer, the major lipid that makes up this bilayer is glycerol-based phospholipid. This fatty membrane allows some small molecules like oxygen and carbon dioxide to enter and leave the cell freely.

Other molecules, such as water and glycerol have a limited capability to enter and leave the cell. In a study by Evers et al. [2], the effect of increased cholesterol precursors in hair follicles led to keratin-plugged follicles; and reduced hair growth. High levels of cholesterol stiffen the cell membrane of the hair follicle, reducing diffusion of molecules such as oxygen, carbon dioxide and water in and out of the cell [3].

A major importance of the physical state of the membrane, is the control of the polarity of the cell which is influenced by how much water can enter and leave the cell. The water permeability of keratin cells that make up the hair and skin effect the overall level of hydration of the essential components that make up the hair and skin.

Several studies showed changes in the lipid content and distribution were responsible for biological events that led to brittle hair and dry skin.  It was also found that the amino acid content of the hair and skin was important for water binding.  In addition, in dry skin of healthy persons, it was found there was a decreased expression of keratin that forms the hair cuticle and the hair cortex occurs (Keratin 1 and Keratin 10) [4].  This lowers the protein on the protective barrier of the hair and the proteins that make up the central canal of the hair fibre.

Dry hair and skin can encourage hair loss

Lipids are essential for transdermal hydration.  Dehydrated skin and hair cells result in damaged and dry skin and hair.

LIPID FUNCTION; OXYGENATION AND OXIDATION

Like other biomolecules, lipids undergo chemical modifications that expand their functional capabilities. Chemical modifications of lipids involve oxygenation of the lipid molecule by the addition of an oxygen molecule to the lipid.  Oxygen can be added purposely with enzymes that work on lipids by a process called oxidation.  In this post we describe the enzymatic addition of oxygen as oxygenation and the non-enzymatic addition of oxygen as oxidation.  Oxidation of lipids remove functionality and can make the lipid a molecule that induces inflammation.

Enzymatically oxygenated lipids constitute a large portion of known oxygenated lipid mediators, being bioactive lipids that are produced locally through specific biosynthetic pathway.   Those derived from oxygenation of polyunsaturated fatty acids such as arachidonic acid include prostaglandins, thromboxanes and leukotrienes, which function in modulating inflammation, the immune response, and homeostasis, and are broadly termed “oxylipins”.

Oxylipins also include multiple oxygenated derivatives of eicosapentaenoic acid and docosahexaenoic acid, of which specific compounds have been termed “specialised pro-resolving mediators” for their roles in the resolution of inflammation.  Oxylipins are also cell signalling molecules commonly used for cell-to-cell communication and for the the mobilisation and cell adhesion required for healthy hair fibre growth.

OXYLIPIN NAME FUNCTION
Sphingosine-1-phosphate A potent messenger derived from ceramide, involved in regulating the mobilisation of calcium and the adhesion of keratin cells to the hair follicle.
Prostaglandins Prostaglandin D2 functionally inhibits hair growth and promotes termination of the hair growth cycle.  Prostaglandin E2 increases the duration of the hair growth cycle and reduces hair shedding.
Steroid hormones Lipid containing hormones such as estrogen and testosterone modulate a number of functions, including the initiation and termination of the hair growth cycle.
OXYLIPIN NAME FUNCTION
Sphingosine-1-phosphate A potent messenger derived from ceramide, involved in regulating the mobilisation of calcium and the adhesion of keratin cells to the hair follicle.
Prostaglandins Prostaglandin D2 functionally inhibits hair growth and promotes termination of the hair growth cycle.  Prostaglandin E2 increases the duration of the hair growth cycle and reduces hair shedding.
Steroid hormones Lipid containing hormones such as estrogen and testosterone modulate a number of functions, including the initiation and termination of the hair growth cycle.

OXIDISED FATS IN THE DIET CAN INDUCE HAIR LOSS CONDITIONS

Lipid oxidation is a process under which reactive oxidative species attack lipids that contain a carbon-to-carbon double bond.  Polyunsaturated fatty acids are especially prone to oxidative damage.  Over the last 40 years, a large body of research has shown the important link between lipid oxidation and its involvement in pathological disease and hair loss.

A study in 2007 found that oxidised fats in milk led to abnormal follicle growth, cycling and the arrest of hair growth [1]. The researchers also found an increase of inflammatory cells in the dermis.  It should be noted that the oxidised products in most milk and dairy products is usually very small, a higher concentration of oxidative products are found in milk and highly processed dairy products exposed to harsh storage conditions where the impact of oxygen, light and low water levels play a big role in oxidative activity.

Karnick et al found an association between a deficiency in peroxisome proliferator–activated receptor-γ was associated with scarring alopecia [5].  This deficiency is known to effect fatty acid storage and lipid uptake, establishing this receptor as a master regulation of lipid sensitivity.  The data showed that a down regulation of the genes related to cholesterol metabolism and perixisome generation were more susceptible to hair loss.  This finding implicates a lacking of any kind of lipid metabolism can result in scarring alopecia.

Another study confirmed that oxidation due to the heating of fats during cooking was significantly linked to hair loss [6].  Lipid oxidation in foods is one of the major degradative processes responsible for losses in food quality. The oxidation of unsaturated fatty acids results in significant generation of dietary advanced lipid oxidation end products which are in part cell toxic and gene toxic compounds. Most of the oxidised fats in foods are expected to come from fats and oils heated at high temperature and more specifically from frying fats.

In response to lipid oxidation, keratin cells will only survive if they have the antioxidant capacity to repair oxidised lipids.  Glutathione is the primary antioxidant used in response to the threat posed by oxidised limits.  To maintain the balance there must be a high enough capacity of this antioxidant.  When this capacity is reached, cell death will occur.  Glutathione is a major reservoir for cysteine, an essential sulphur rich amino acid for hair growth.  Depletion of glutathione impacts the availability of the sulphur required for the sulphur to sulphur bonds that are responsible for the mechanical strength of the hair fibre.

Polyunsaturated fats and hair loss

Polyunsaturated fats are a major source of oxidised limits in the diet due to their low stability when exposed to heat. Foods high in polyunsaturated fat include energy bars, nuts, crisps and heavily processed meat.

THE HAIR GROTH CYCLE DEPENDS ON PROPER LIPID METABOLISM

Hair follicle development is organised by a number of coordinated signals from neighbouring cells.  The activation of Hedgehogs and Wnts are required for stable hair growth and for the start of new hair growth in dormant follicles.

Hedgehogs are proteins that are able to induce hair growth by reactivating embryonic programs in adult tissue allowing hair growth in a hair follicle niche that has been biologically inactive.  Hedgehogs can stimulate hair growth in inactive hair follicle within several weeks.

Wnts are a group of glycoproteins that control a variety of growth process throughout the body, they are especially important for hair growth.  When Wnts bind to specific cells they encourage DNA transcription, in hair cells this will encourage the production of lots and lots keratin.

Another mechanism linking hair follicle survival to lipid metabolism is the lipid modification of cell signalling proteins such as the Hedgehogs and Wnts, these proteins are necessary for the generation of the hair follicle and normal hair follicle cycling.  One end of the Hedgehog and Wnt proteins are modified by a fatty acid making them insoluble and biochemically active.

Clinical trials have shown that removing this lipid attachment disables the function of both Hedgehogs and Wnts.  High concentrations of cholesterol precursors have also been implicated in disruption to the modification of these cell signalling proteins.

Wnts are signalling proteins

Wnts are essential for hair follicle development. Wnts are signalling proteins that undergo lipid modification to enable functionality.

CHOLESTEROL METABOLISM AND THE RISK OF HAIR LOSS

Cholsesterol is essential for life, around 80% of cholesterol is produced in the liver and each living cell in the body is able to synthesise cholesterol using a complex 37-step process.  The first 18 steps are known as the mevalonate or HMG-CoA reductase pathway followed by 19 additional steps.  A human adult male weighing around 68kg will normally synthesise about 1 gram of cholesterol per day.

Most cholesterol from dietary sources is poorly absorbed in the gut, when cholesterol is absorbed the body responds by reducing cholesterol synthesis after approximately 7 hours.  Cholesterol synthethesis is regulated by he endoplasmic reticulum (responsible for the transport of lipids and proteins) and the mitochondria (the energy plant of all cells).

Cholesterol is used to make products essential for cell survival such as testosterone and vitamin D.  High levels of cholesterol and cholesterol precursors have been found in populations with population with low testosterone and low vitamin D.

Low zinc levels are also related to low testosterone and low vitamin D levels, research has shown a direct correlation between zinc levels and cholesterol levels [7]. Pharmacological  doses of between 35 mg and 50 mg of elemental zinc have been shown to be effective in lowering cholesterol but lower doses of 15 mg (the RDA for zinc) have no noticeable effect [8].

Zinc is a major component of membrane-bound transcription factor peptidase site 2.  This metalloprotease is essential for the metabolism  of cholesterol within the cell.  Supplementation with zinc is likely to increase cholesterol conversion to vitamin D and testosterone via this transcription factor.

High levels of cholesterol also increase the activity of matrix metalloproteases that result in the degradation of the collagen fibres within the extracellular matrix resulting in thinner hair that sheds prematurely.

A study conducted on 827 Italian factory workers in 1990 showed that men with no hair loss had an average cholesterol level of 5.369 mmol/L, men with receding hairlines had an average cholesterol level of 5.387 mol/L and men with more sever hair loss had an average cholesterol level of 5.521 mol/L.

The central finding of one study [9], was that excess cholesterol within the hair follicle niche can trigger an innate immune response that leads to the induction of Toll-like receptor and Interferon gamma gene expression.

This leads to the activation and recruitment of T cells and macrophages that surround the hair follicles and initiate an inflammatory response resulting in the hair less lesions seen in alopecia areata.

Hair loss associated with abnormal cholesterol metabolism is also seen in women with low, normal or high levels of cholesterol. It appears the ratio of high density lipoproteins compared to low density lipoproteins is the factor that affects hair growth.

Cholesterol and hair loss

Cholesterol is required for the synthesis of testosterone and vitamin D. Abnormal levels of cholesterol are associated with hair loss in men and women.

CALCULATING THE RISK OF HAIR LOSS BY CALCULATING HDL TO LDL RATIO

Cholesterol is insoluble in water and needs to be transported by lipoproteins in the blood. There are two main types of cholesterol protein carrier: high density lipoprotein (HDL) and low density lipoprotein (LDL.  HDL is known as “good cholesterol because this lipoprotein transports cholesterol to your liver to be expelled from the body.  LDL is known as “bad cholesterol” because it transports cholesterol throughout the body. These definitions are somewhat arbituary as good and bad is defined by transport only.

Arguably a lower level of HDL could show functional use of cholesterol by the conversion to vitamin D and testosterone.  By this standard HDL would become “bad” as it shows lack of utilisation by the body and LDL would be seen as good as it shows the capacity of the body to provide the materials for the creation of vitamin D and testosterone.  This theory is supported by the fact that high levels of HDL can be seen in patients that have previously had a heart attack.

High levels of HDL are linked to other conditions including: thyroid disorders, alcohol consumption and inflammatory disease.  Zinc supplementation has been shown to lower HDL specifically, potentially due to its impact on inflammation and alcohol tolerance.

The ratio of HDL to LDL has been significantly linked to hair loss in women, this further suggests the invalidity of the “good vs bad” determination.  Doctors calculate an individual’s cholesterol ratio by dividing their total cholesterol by their HDL. The optimal ratio is between 1 and 3.5, a higher ratio is linked to an increased risk of hair loss.

This ratio determination would further demonstrate that HDLand LDL by itself can not be taken as a negative or positive value as a 1:1 ratio of HDL and LDL is a more significant predictor of potential hair health than the individual measurements of either.

HDL and LDL levels influence hair loss

Cholesterol is carried by lipoproteins in the blood (HDL and LDL). Higher levels of cholesterol are associated with hair loss in men, in women the ratio of HDL to LDL is a major contributor to hair loss.  HDL represents cholesterol that has not undergone the necessary biochemical transformation into vitamin D and testosterone.

LIPIDS ARE AN ESSENTIAL ENERGY SOURCE FOR ALL CELLS OF THE BODY

Adipose tissue is a type of connective tissue made up of lipid cells.  This specialised tissue plays a role in the control of metabolism as well as the storage of lipids as an energy source.  Adipose tissue is a critical regulator of energy homeostasis by acting as a calorie reservoir.

When there is an excess of calories, these are transported with LDL and stored in the tissue as trialglycerides, when there is a deficit of calories, the triglycerides are mobilised and transported around the body.  In response to changes in energy status adipose tissue is continually remodelled though the changes in number and size of fat cells that hold the lipids.

Lipids are used to provide energy to cells when glucose stores are low.  Lipids are released from adipose tissue in the form of triglycerides and travel round the body.

The release of lipids from cells induced by a catabolic process called lipolysis.  Lipolysis is stimulated by several hormones including testosterone, cortisol, growth hormone and adrenaline.  Perilipin is a protein that coats adipose cells and prevents lipolysis.

Testosterone is required to activate perelipin and enable circulation of lipids.  If there is not enough available lipid in circulation to provide cells with the fuel they need, then cell function will be reduced.  In keratin cells that make up the hair fibre, this will result in the termination of the hair growth cycle.

This lack of energy can be induced by fasting and tends to happen after 3 hours of carbohydrate ingestion.  Dieting and going for long periods between meals will increase this energy deficit.  This energy deficit will result in a condition know as telogen effluvium, a typeof hair loss characterised by premature shedding of the hair fibre.  If this continues for a long period of time, hair loss will become more established and appear as diffuse hair loss.

In the human body there are two major types of adipose tissue.  Adipose tissue that is used for thermal regulation and energy burning is brown (due to an abundance of mitochondria), white adipose tissue is responsible for the synthesis of hormones and inflammatory cascades.
Testosterone and DHT for hair follicle energy

Testosterone increases lipolysis to provide energy for cells. Higher levels of testosterone enables the breakdown of fats for energy.  Dihydrotestosterone (DHT) is unable to liberate fatty acids and contributes to low energy supply to follicles and obesity.

INFLAMMATION, WHITE ADIPOSE TISSUE AND THE LINK TO HAIR LOSS CONDITIONS

Adipose tissue was historically considered merely a calorie reservoir, but his concept was revised following the discovery of leptin. Leptin is released in response to changes in nutritional status, after leptin, other substances (cytokines, peptides and hormones) secreted by adipose tissue were discovered and indicates adipose tissue acts as an endocrine organ involves in maintaining energy status.

Disorders of lipid metabolism leads to abnormal lipid storage and an abnormally slow release of lipids for energy use.  These excess stored lipids go on to produce an abnormal level of hormones such as leptin, adiponectin, estrogen and resistin.  Lipid cells can also release cytokines such as tumour necrosis factor and interleukin 6.  These hormones generally increase inflammation and slow down metabolism.

Anatomically white adipose tissue is deposited subcutaneous fat (below the skin) and visceral fat (around internal organs).  Visceral fat in the abdominal cavity is further subdivided into mesenteric, omental, perirenal and peritoneal depots.

The key functions of white adipose tissue are insulation (and also a secondary energy source to brown adipose tissue).  However, excess white adipose tissue is linked to metabolic conditions such as insulin resistance and type II diabetes.  These conditions are closely associated with hair loss conditions such as androgenic alopecia, scarring alopecia and alopecia areata.

Mesenteric and omental adipose tissue are specifically important for insulin resistance and increased levels of fat in the liver due to the close proximity and exposure of hormonal adipose tissue secretions via the portal vein.

The pro-inflammatory response in adipose tissue ultimately leads to insulin resistance.  The degree of inflammation depends on the dynamics between resident immune cells within the tissue.  Regulatory T-cells protect adipose tissue through cell-to-cell interactions as well as the secretion of anti-inflammatory cytokines (interleukin-10 and  transforming growth factor beta).

Macrophages and natural killer T-cells also cooperate to reduce inflammatory signals from adipose tissue.  Zinc is a powerful regulator of immune cells and can reduce the number of inflammatory signals sent out by these immune cells.

Leptin, inflammation and hair loss

White adipose tissue secretes leptin. Higher levels of white adipose tissue leads to an increase activation of immune cells and an increase in inflammation.

REVERSING THE EFFECT OF POOR LIPID METABOLISM ON THE HAIR FOLLICLE

Insulin-like growth factor is able to modulate the levels of cholesterol around the hair follicle niche. Hair growth depletes the amount of cellular cholesterol and its steroid hormone metabolites in the membrane.

Phytoestrogen therapy lowers cholesterol around the hair follicle and increases hair fibre growth [10].  When phytoestrogens were trialled, the decrease in cholesterol precursors was quicker in patients with higher cholesterol than those with lower cholesterol suggesting the return of cholesterol within the required narrow range was necessary for normal cell function rather than an overall cholesterol precursor reduction [11].

Lowering levels of stored fat can help to normalise high triglyceride levels.  When a person starts or maintains an exercise regime, the body will use the energy in the stored cells to fuel the new activity.  Building lean muscle will also increase the utilisation of stored fat.
Zinc supplementation supports the generation of testosterone and vitamin D from cholesterol.  Testosterone and vitamin D support the hair growth cycle and also removes cholesterol from the serum lowering the LDL to HDL ratio to optimal levels reducing cellular stress.

THE FINAL WORD

Balancing lipid levels will help with new hair growth and will reduce the severity of current hair loss. If you are worried that your hair loss may be due to an unbalanced lipid profile talk to your doctor and request a lipid profile that will cover: triglycerides, HSL, LDL HDL/LDL ratio and total cholesterol.

REFERENCES

  1. Wan et al.  Maternal PPARγ protects nursing neonates by suppressing the production of inflammatory milk. 2007)
  2. Evers et al. Hair growth defects in Insig-deficient mice caused by cholesterol precursor accumulation and reversed by simvastatin. J Invest Dermatol. 2010;130:1237–48.
  3. Nguyen, T.V.N. and Brownell, W.E., 1998. Contribution of membrane cholesterol to outer hair cell lateral wall stiffness. Otolaryngology—Head and Neck Surgery, 119(1), pp.14-20.
  4. M. Engelke, J.M. Jensen, S. Ekanayake-Mudiyanselage, E. Proksch. Effects of xerosis and ageing on epidermal proliferation and differentiation. British Journal Dermatology, 137 (1997), pp. 219-225
  5. Karnik P, Tekeste Z, McCormick TS et al. (2009) Hair follicle stem cell-specific PPARγ deletion causes scarring alopecia. J Invest Dermatol 129:1243–57
  6. Kanner, J., 2007. Dietary advanced lipid oxidation endproducts are risk factors to human health. Molecular nutrition & food research, 51(9), pp.1094-1101.
  7. Koo, S.I. and Williams, D.A., 1981. Relationship between the nutritional status of zinc and cholesterol concentration of serum lipoproteins in adult male rats. The American journal of clinical nutrition, 34(11), pp.2376-2381.
  8. Age-Related Eye Disease Study Research Group, 2002. The effect of five-year zinc supplementation on serum zinc, serum cholesterol and hematocrit in persons randomly assigned to treatment group in the age-related eye disease study: AREDS Report No. 7. The Journal of nutrition, 132(4), pp.697-702.
  9. Panicker, S.P., Ganguly, T., Consolo, M., Price, V., Mirmirani, P., Honda, K. and Karnik, P. 2012. Sterol intermediates of cholesterol biosynthesis inhibit hair growth and trigger an innate immune response in cicatricial alopecia. PloS one, 7(6), p.e38449.
  10. Taku, K., Umegaki, K., Sato, Y., Taki, Y., Endoh, K. and Watanabe, S., 2007. Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials. The American journal of clinical nutrition, 85(4), pp.1148-1156.
  11. Genes Dev 21:1895–908Palmer, M.A., Blakeborough, L., Harries, M. and Haslam, I.S., 2020. Cholesterol homeostasis: Links to hair follicle biology and hair disorders. Experimental dermatology, 29(3), pp.299-311.

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